Cross-linked agent for generation of a long-lasting satiety effect and method for the production of the said

ABSTRACT

The invention relates to an orally administerted agent containing stable, uronic acid-containing polysaccharides cross-linked to each other and in the form of a sponge-like structure which dissolves poorly in water and/or gastrointenstinal liquids or can be poorly resorbed. A method for the production and application of the said agent is also disclosed

This is the National Phase Application of PCT EP00/08646 filed Sep. 5,2000.

The present invention relates to a composition for producing a satiationeffect.

Numerous attempts have been made by medical means to break downexcessive accumulations of fat in the human body, or to prevent themdeveloping. There are, for example, appetite suppressants which attemptby biochemical means to induce in the body a disinclination to takefood. These compositions have in some cases considerable harmful sideeffects.

Besides the numerous dietary products which have been proposed, thereare also mechanical and electromechanical means intended specifically tobreak down fat and build up muscle. However, the effect of such means isvery doubtful.

German Patent DE 402,5912 discloses a composition for oral intake whichconsists of a container which is soluble in the stomach and releases thecontents. This container is filled with a substance whose volumeincreases after it is released in the stomach, and thus it induces afeeling of satiation in the body.

From the prior art a number of elastic materials are already known thatcan be compressed on passage through the esophagus and which can, afterleaving the esophagus, be decompressed in water and/or gastrointestinalfluid. Such sponge-like structures are taken to mean foams which consistof gas-filled spherical/polyhedral cells which are limited by highlyviscous or solid cell walls. It is possible to employ according to theinvention both naturally occurring sponges and synthetically preparedsponge-like structures.

Natural materials which are already used are collagen and cellulose.However, these abovementioned materials are relatively expensive rawmaterials. Both materials require complex isolation or work-up processeswhich, in addition, are very environmentally polluting. The latterapplies especially to cellulose, the isolation of which means that largeamounts of acids have to be employed.

Soluble collagen is isolated from animal hides, for example, preferablyyoung cattle or pigs, since the soluble collagen content in the animalbecomes ever smaller with increasing age. This is also only possiblewith complex isolation and work-up processes.

Not least since the discovery of a number of diseases in pigs andcattle, which are suspected to be transmissible to humans, in particularthe cattle disease BSE, and a possible risk of infection for humans, theacceptance of such collagen-containing products by the end consumer hasfallen drastically.

It is an object of the present invention, therefore, to provide amaterial for preparing a composition for producing a long-lastingsatiation effect, which material does not have the abovementioneddisadvantages.

This is achieved according to the invention by a composition for oralintake comprising uronic-acid-containing polysaccharides stablycrosslinked to one another in the form of a sponge-like structure whichis characterized in that it is slightly soluble or of low absorbabilityin water and/or gastrointestinal fluids.

According to the invention the uronic-acid-containing polysaccharidesare crosslinked to one another by ionic bonds and in addition are stablycrosslinked to one another by covalent bonds. Particularly preferredpolyuronic acid-containing-polysaccharides are alginic acids and theirsalts (alginates). However, low degree of esterification pectins,xanthan, tragacanth, chondroitin sulfate and all otheruronic-acid-containing compounds can also be used according to theinvention.

Alginic acid is a linear polyuronic acid of alternating parts ofD-mannuronic acid and L-guluronic acid which are linked to one anotherby β-glycosidic bonds, the carboxyl groups not being esterified. Onemolecule of alginic acid can be composed of about 150-1 050 uronic acidunits, where the mean molecular weight can range from 30-200 kDa.

The polysaccharide alginic acid is a constituent of cell walls of brownalgae. The alginic acid content can make up to 40% of the dry matter ofthe algae in this case. The alginic acid is produced by alkalineextraction with methods known per se according to the prior art. Theresultant pulverulent alginic acid is thus purely of plant origin andhas high biocompatibility. It can absorb 300 times its own weight ofwater, forming highly viscous solutions. In the presence of polyvalentcations, alginic acid forms gels. The formation of alginate gels in thepresence of divalent cations, such as calcium or barium, is described inShapiro I., et al. (Biomaterials, 1997, 18: 583-90). The latter is notsuitable for use in biomedicine, however, on account of its toxicity. Inaddition to calcium chloride, calcium gluconate also provides suitabledivalent cations. In general, all physiologically safe polycations canbe used, in particular divalent cations. The unbranched concertina-likealginate chains are fixed by ionic bonds via the free bonding positionsof the cations, preferably calcium ions (FIG. 1). This produces athree-dimensional network in which the divalent cations are situatedlike “eggs in an eggbox” as in the “egg-box model” presented in Smidsrodet al. (Trends in Biotechnology, 1990, 8: 71).

The sponge-like or sponge-shaped structures are produced by methodsknown per se from the prior art. Depending on the starting materialemployed, in the simplest case, a foam can be obtained by blowing, bybeating, shaking, spraying or stirring in the relevant gas atmosphere.In the case of polymers, the foam structure is produced by chemicalreactions. Thus, for example, polyurethanes are foamed by adding blowingagents which decompose at a defined temperature during processing, withgas formation, or by addition of liquid solvents during thepolymerization. The foaming takes place either on leaving the extrusiondie, that is to say following the extrusion or injection molding, or inopen molds. The curing takes place under the conditions characteristicof the respective chemical compound of the material.

An indispensable prerequisite for the usability of the material is thatit can be compressed without breaking the cell walls. This is because inorder to be able to use the inventive material for oral intake, thefoam-like or foamy material must be directly compressible on passagethrough the esophagus. In particular, no trouble must occur on passagethrough the esophagus.

A particular advantage of the present invention is that the alginatescrosslinked according to the invention are more flexible and softer, andas a result have very much more favorable mechanical properties forgastrointestinal application than the materials previously available onthe market. For the user this is accompanied by the advantage ofimproved tolerance, so that even in the case of patients having mucosallesions, neither a feeling of pressure nor mucosal irritation is caused.

For the selection of the material and the type of foam formation, it isfurthermore essential that the material remains swellable withoutdestroying the cell walls. After passage through the esophagus, thesponge-like structure is to resume at least the size which it had beforeentry into the esophagus. If appropriate, the material may also swell toa size which goes beyond the original volume.

The sponge-like structure can have any desired shape and size in thecompressed and decompressed states. However, preference is given tocuboid or rectangular or round embodiments.

Preferably, the material is designed so that the sponge-like structurecan be compressed to ½ to {fraction (1/100)}, preferably ¼ to {fraction(1/50)}, particularly preferably {fraction (1/10)} to {fraction (1/20)},of its volume or of its size. Under physiological conditions, thecompressed material, after passage through the esophagus, is to be ableto expand, preferably to two to twenty times, particularly preferably tofour to fifty times, and very particularly preferably to ten to twentytimes, its volume.

As material for the sponge-like structure, according to the inventionnatural, semisynthetic or synthetic polymers can be used, which, inaddition, can be crosslinked by stable crosslinks.

Various processes are known from the prior art for crosslinkingpolymers. Thus, for example, the free-radical polymerization oflactose-O-(p-vinylbenzyl)oxime for forming hydrogels is described inZhou, W-Z, et al. (Macromolecules, 1997, 30: 7063-7068) and apolymerization of N-vinylpyrrolidone by electron-beam irradiation isdescribed in Rosiak, J. M. (J Contr Rel., 1994, 31: 9-19). In addition,for example, crosslinked polymers of saccharide acrylates orpoly(2-hydroxyethylmethacrylate)gelatin and also collagen or chitosanare known (Martin, B. D., et al. (Biomaterials, 1998, 19: 69-76; Santin,M., et al. (Biomaterials, 1996, 17: 1459-1467); Weadock, K. S., et al.(J Biomed Mater Res, 1995, 29: 1371-1379); Groboillot, A., et al.(Biotech Bioeng, 1993, 42: 1157-1163)).

Examples of starting materials particularly suitable according to theinvention are uronic-acid-containing polysaccharides which still havefree reactive groups, preferably carboxyl groups and/or hydroxyl groups,for forming stable crosslinks, for example ester bonds. Very highpreference is given here to alginic acids, low degree of esterificationpectins, xanthan, tragacanth, chondroitin sulfate and alluronic-acid-containing compounds and their salts.

Crosslinking alginates by polyvalent cations is described in Shapiro L.et al., Biomaterials, 1997, 18:583-590. However, these compounds areunstable in water or a surrounding medium having a calcium concentrationless than 3 mmolar, since the calcium is extracted from the chaincluster and/or may be displaced by other (monovalent) ions. This leadsto a dissolution of the crosslinking between the concertina-likepolyuronic-acid-containing polysaccharide chains. It is a disadvantagehere that the alginates which are only crosslinked by ionic bondsdissolve relatively rapidly in water and/or gastrointestinal fluids andare thus not suitable for producing a satiation effect. A particularadvantage of the inventive composition is stable crosslinking bycovalent bonds, in particular ester bonds, the formation of which iscatalyzed by mineral acids. Covalently linked alginate molecules havealso already been described in Moe et al. (Food Hydrocolloids, 1991,119). However, the preparation process requires relatively long reactiontimes. In addition, resultant products, owing to the chemicals used fortheir production, are toxic and are thus not suitable for the fields ofapplication according to the invention.

The inventive composition can comprise, inter alia, pharmaceuticallyactive substances, foodstuffs or food supplements, for example vitamins,dietary fiber, proteins, minerals and other food constituents, taste andstimulant substances or flavorings.

In addition to said substances, it is also possible to add otherancillary substances to the carrier material. Inter alia,release-slowing substances may additionally be suitable in the casewhere pharmaceutically active substances are used.

In addition, the compositions according to the present invention canadditionally contain fillers, disintegrants, binders and lubricants andalso excipients.

Active compounds can also be introduced into the sponge-like structure.

For the purposes of the invention, active compounds are all substanceshaving a pharmaceutical or biological action. Examples arebetamethasone, thioctic acid, sotalol, salbutamol, norfenefrine,silymarin, dihydroergotamine, buflomedil, etofibrate, indomethacin,oxazepam, beta-acetyldigoxin, piroxicam, haloperidol, ISMN,amitriptyline, diclofenac, nifedipine, verapamil, pyritinol,nitrendipine, doxycycline, bromhexine, methylprednisolone, clonidine,fenofibrate, allopurinol, pirenzepine, levothyroxine, tamoxifen,metildigoxin, o-(beta-hydroxyethyl)rutoside, propicillin, aciclovirmononitrate, paracetamol, naftidrofuryl, pentoxyfylline, propafenone,acebutolol, L-thyroxine, tramadol, bromocriptine, loperamide, ketotifen,fenoterol, Ca dobesilate, propranolol, minocycline, nicergoline,ambroxol, metoprolol, beta-sitosterol, enalapril hydrogen maleate,bezafibrate, ISDN, allopamil, xanthinol nicotinate, digitoxin,flunirazepam, bencyclane, dexapanthenol, pindolol, lorzepam, diltiazem,piracetam, phenoxymethylpenicillin, furosemide, bromazepam, flunarizine,erythromycin, metoclopramide, acemetacin, ranitidine, biperiden,metamizole, doxepin, dipotassium chlorazepate, tetrazepam, estramustinephosphate, terbutaline, capt opril, maprotiline, prazosin, atenolol,glibenclamide, cefaclor, etilefrine, cimetidine, theophylline,hydromorphone, ibuprofen, primidone, clobazam, oxaceprol,medroxyprogesterone, flecainide, Mg pyridoxal 5-phosphate glutamate,hymecromone, etofylline clofibrate, vincamine, cinnarizine, diazepam,ketoprofen, flupentixol, molsidomine, glibornuride, dimetindene,melperone, soquinolol, dihydrocodeine, clomethiazole, clemastine,glisoxepide, kallidinogenase, oxyfedrine, baclofen,carboxymethylcysteine, thioridazine, beta histine, L-tryptophan, myrtol,bromelains, prenylamine, salazosulfapyridine, astemizole, sulpiride,benserazide, dibenzepin, acetylsalicylic acid, miconazole, nystatin,ketoconazole, Na picosulfate, colestyramine, gemfibrozil, rifampicin,fluorocortolone, mexiletine, amoxicillin, terfenadine,mucopolysaccharide polysulfates, triazolam, mianserin, tiaprofenic acid,amezinium methyl sulfate, mefloquine, probucol, quinidine,carbamazepine, Mg L-aspartate, penbutolol, piretanide, amitriptyline,cyproterone, Na valproate, mebeverine, bisacodyl, 5-aminosalicylic acid,dihydralazine, magaldrate, phenprocoumon, amantadine, naproxen,carteolol, famotidine, methyldopa, auranofin, estriol, nadolol,levomepromazine, doxorubicin, meclofenoxate, azathioprine, flutamide,norfloxacin, fendiline, prajmalium bitartrate, escin.

Further examples are the following active substances: acetaminophen(=paracetamol), acetohexamide, acetyldigoxin, acetylsalicylic acid,acromycin, anipamil, benzocaine, beta-carotene, chloramphenicol,chlordiazepoxide, chlormadinone acetate, chlorthiazide, cinnarizine,clonazepam, codeine, dexamethasone, diazepam, dicumarol, digitoxin,digoxin, dihydroergotamine, drotaverine, flunitrazepam, furosemide,gramicidin, griseofulvin, hexobarbital, hydrochlorothiazide,hydrocortisone, hydroflumethazide, indomethacin, ketoprofen, lonetil,medazepam, mefruside, methandrostenolone, methylprednisolone,methylsulfadiazine (=sulfaperin), nalidixic acid, nifedipine,nitrazepam, nitrofurantoin, nystatin, estradiol, papaverine, phenacetin,phenobarbital, phenylbutazone, phenytoin, prednisone, reserpine,spironolactone, streptomycin, sulfadimidine (=sulfamethazine),sulfamethizole, sulfamethoxazole, (=sulfameter), sulfaperin,sulfathiazole, sulfisoxazole, testosterone, tolazamide, tolbutamide,trimethoprim, tyrothricin, vitamins, minerals.

Active compounds which also come into consideration are those havingprophylactic action, for example in the field of tumor therapy.

In addition to said active compounds, it is also possible to add otherancillary substances to the carrier material. Inter alia,release-slowing substances can additionally come into consideration.

Release-slowing ancillary substances which can be used are essentiallywater-insoluble ancillary substances or mixtures thereof, such aslipids, inter alia fatty alcohols, for example cetyl alcohol, stearylalcohol and cetostearyl alcohol; glycerides, for example glycerolmonostearate or mixtures of mono-, di- and triglycerides of vegetableoils; hydrogenated oils, such as hydrogenated castorr oil orhydrogenated cottonseed oil; waxes, for example beeswax or carnauba wax;solid hydrocarbons, for example paraffin or earth wax; fatty acids, forexample stearic acid; certain cellulose derivatives, for example ethylcellulose or acetyl cellulose; polymers or copolymers, such aspolyalkylenes, for example polyethylene, polyvinyl compounds, forexample polyvinylchloride or polyvinylacetate, and alsovinylchloride-vinylacetate copolymers and copolymers with crotonic acid,or polymers and copolymers of acrylates and methacrylates, for examplecopolymers of acrylates and methyl methacrylate.

The resultant material which is slightly soluble or has lowabsorbability in water and/or gastrointestinal fluids can then becompressed. This can be achieved by pressing, rolling or comparablemethods. In addition, the material can be compressed by chewingmovements during the oral intake of the material.

Before, during or after the preparation of the sponge-like structure,the material can be loaded, for example, with the abovmentioned activesubstances. All conventional methods are suitable for this purpose. Inthe simplest case, this can take place during the preparation phase ofthe sponge material by mixing carrier material and active substance.Also, these substances can be applied to the surface.

The sponge-like structure thus prepared can, in a preferred embodimentof the invention, be encased with the abovementioned substances. That isto say either a container, for example a capsule, is produced from thesubstance and the sponge-like structure is introduced into this, or thesubstance is applied directly onto the structure, for instance byimmersion, spraying, spreading or similar methods. In another embodimentof the invention, the sponge-like structure is introduced into thesubstance. This can be achieved, for example, by impregnation.

The purpose of the inventive process is to obtain a composition which issufficiently compressed on passage through the esophagus and is notdecompressed until in the stomach. This purpose is achieved by saidprocess steps.

In contrast to other food/food supplement/dietary or drug products whichare rapidly decomposed in the stomach or pass into it already in acomminuted state, the sponge or foam body which is prepared in thedescribed manner and consists of natural, semisynthetic or syntheticpolymers retains its original shape for several hours due to particularcrosslinking points, in particular covalent bonds. Owing to thedecompression of the inventive composition in the stomach, the stretchreceptors of the stomach are excited, which triggers a feeling ofsatiation. The inventive sponge is dissolved only slightly or absorbedonly to a limited extent in the stomach in the course of this.

In addition, the present invention relates to a process for preparingcompositions for producing a long-lasting satiation effect. In theprocess, polyuronic-acid-containing polysaccharides are crosslinked viaionic bonds, frozen, freeze-dried, stably crosslinked via covalentbonds, then dried and, if appropriate, pressed. Particularly preferablyhere the unbranched polyuronic-acid-containing polysaccharides used arealginic acids and their salts. In addition, pectins, xanthan,tragacanth, chondroitin sulfate and all other uronic-acid-containingcompounds or their salts are also conceivable.

According to the invention, alginic acids or their salts are used inconcentrations of 0.3 to 10% by weight, preferably 0.5 to 5% by weight,particularly preferably at concentrations of 1 to 3% by weight.

In addition, it is essential to the invention that by immersing thesponge-like structure in mineral acids, preferably hydrochloric acid,after the freeze-drying, additional stable crosslinking points areintroduced into the sponge material by forming covalent ester bonds(FIG. 2). In this case, according to the discretion of those skilled inthe art, at least catalytic amounts of mineral acids are used, but atmost an amount such that the material is not broken down into itsconstituents by acid hydrolysis. Particular preference is given to aconcentration of 0.1 mol/l of mineral acid, in particular hydrochloricacid. The stable crosslinking due to mineral acids causes solubility ofthe sponge body in water and/or gastrointestinal fluids to be onlyslight for a long time. This slight solubility is a prerequisite forlong residence of the sponge in the stomach and the long-lastingsatiation effect caused as a result.

The invention is not restricted to the described process, but alsoapplies to all other processes in which sponges or sponge-likestructures are prepared which are to, or can, achieve a long-lastingsatiation effect due to only slight solubility in water and/orgastrointestinal fluids and the resultant long residence time in thestomach.

The inventive composition is taken orally. The solid sponge or solidfoam body passes through the mouth, throat and esophagus by the additionof beverage and gentle chewing or swallowing movements, and swells againin the stomach, preferably to its original volume, owing to the gastricfluid. If appropriate, the volume may alternatively be greater than orless than the original volume.

The oral intake of the inventive composition means that the solid spongeor solid foam body, owing to the only slight solubility in the stomach,resides for several hours in the stomach. As a result, a long-lastingfeeling of satiation or repletion can be achieved, which results in areduced food intake. However, the composition can also be used in thefields of pharmacy and/or health, preferably (dietetic) nutrition orfood supplementation. For this purpose the composition comprises theabove-described active compounds or foodstuffs.

Depending on the degree of satiation desired, a different number ofsponge bodies can be taken daily at differing time intervals. The“stretch receptors” triggered by the sponge volume situated in thestomach generate via the diencephalon a satiation effect which decreasesagain only when the stomach is emptied. It is thus possible to controlthe period of satiation by the length of residence of the bulk sponges.

In addition, the present invention relates to the use of the inventivecompositions for preparing compositions to produce a satiation effectand for preparing drugs which can be administered orally, foodstuffs,food supplements or dietetic foods loaded with active compounds.

In addition, the inventive compositions can also develop their actionafter passage through the stomach, that is to say in the intestine. Herethe composition acts by exciting the stretch receptors in the intestinalwall, in particular stimulating intestinal activity.

In a particular embodiment of the invention, the composition can also bedesigned such that the decompression does not take place until it is inthe intestine. That is to say the composition in this case does notdevelop its action in the stomach, but only in the intestine. For thispurpose, preferably, it is envisaged to provide the polymers with acompound which does not dissolve in the stomach, but only in theintestine, so that the compressed sponge-like structure is also not ableto decompress until it reaches there.

The dissolution of the compound is affected in this case by variousparameters, in part also prevailing simultaneously in the intestine, forexample pH, pressure, redox potential and enzymatic dissolution via theintestinal flora. In addition, the residence time of the composition inthe intestine also affects the rate at which the compound dissolves.

For preference, the compound dissolves at a pH between 5 and 10,preferably between 7 and 9, particularly preferably between 5.5 and 8.5.Dissolution in the pH environment of the intestine at a pH between6.4±0.6 and 7.0±0.7 is most preferred. In particular, those compoundsare suitable which dissolve depending on the redox potential, enzymaticactivities and pressure.

The compound is applied to the sponge-like structure according to theinvention preferably in the form of a coating which, if appropriate, canalso be made up of a plurality of layers. The minimum layer thicknesshere can vary considerably and is dependent on the film-former used andits composition. Osterwald H. et al. (Acta Pharm Technol, 1980, 26:201-209) describes, for example, a minimum layer thickness of 46 μm forthe preparation of a film-former in organic solvents, preparation withan ammonium salt solution requires a layer thickness of 161 μm, as anemulsion 46 μm and as a latex dispersion 52 μm. According to theinvention, the layer thickness is from 10 μm to several millimeters,preferably from 15 μm to 3 mm.

However, instead of a coating applied directly to the structure, thesponge-like structure can be introduced into a container which dissolvesunder the above-described conditions. That is to say the container isstable in the stomach, but dissolves in the intestine.

In another variant of the invention, the compound can be introduced intothe sponge-like structure. This may be achieved, for example, byimpregnation in a solution of the compound or by adding the compoundduring preparation of the sponge-like structure. Obviously, a structureimpregnated, for example, in such a manner can additionally be providedwith a coating of the compound. In addition, the impregnated structurecan also be introduced into the above-described container. In addition,the structure can be introduced into a container which itself is coatedor impregnated with the compound or into which the compound isintroduced.

The time and location of the dissolution of the compound may beinfluenced by the selection and combination of the compounds, whichachieves targeted release of the sponge-like structure in the intestineand, in particular, in the various intestinal sections, such as thejejunum, ileum and colon. The solubility of the compounds can depend onone or more factors, for example pH, time of exposure, redox potentialof the intestine, enzymatic activities of the intestinal flora, orpressure which is produced by intestinal peristalsis. The variouspossibilities for controlling the release of active compounds aredescribed extensively. The pH-dependent solubility is described, forexample, in Marvola et al., Eur J Pharm Sci, 1999, 7:259-267 and Khan Ziet al., J Controlled Release, 1999, 58:215-222. Pozzi F. et al., JControlled Release, 1994, 31:99-108; Wilding I R et al., Pharmacol Ther,1994, 62:97-124; Niwa K. et al, J Drug Target, 1995, 3:83-89 and U.S.Pat. 4871549 disclose systems which release the active compounds as afunction of time. Examples of systems having a combined pH and timedependency are described in Rodriguez M. et al., J Controlled Release,1998, 55:67-77 and Gazzinga A. et al., STP Pharm Sci, 1995, 5:83-88. Thedissolution of compounds due to changed redox potential in the intestineis dealt with by Bronsted H. et al., Pharm Res 1992, 9:1540-1545; Yeh PY et al., J Controlled Release, 1995, 36:109-124; Shanta K L et al.,Biomaterials, 1995, 16:1313-1318 and Kimura Y et al., Polymer, 1992,33:5294-5299. Examples of systems which are released by the enzymes ofthe intestinal flora are described in Ashford M et al., J ControlledRelease, 1994, 30:225-232; Fernandez-Hervas M J et al., Int J Pharm,1998, 169:115-119; EP-0460921; U.S. Pat. No.-4,432,966 and Milojevic Set al., J Controlled Release, 1996, 38:75-84. The dissolution of systemsdue to the pressure of intestinal peristalsis is covered in Muraoka M etal., J Controlled Release, 1998, 52:119-129.

Preference is given according to the invention to the followingcompounds and their combinations which are, however, in no way limitingfor the present invention: hydroxypropyl methyl cellulose phthalate(HPMCP 55), hydroxypropyl methyl cellulose acetate succinate (AqoatAS-MF, Aqoat AS-HF), 1:1 copolymer of methacrylic acid and ethylacrylate (Eudragit®L), copolymer of vinyl acetate and crotonic acid(Coating CE 5142), cellulose acetate phthalate (CAP, Aquateric),methacrylate copolymers (Eudragit®S), shellac, Time Clock System®,carnauba wax, hydroxypropyl methyl cellulose (TC-5), Pulsincap®,polyethylene glycol, crosslinked polyethylene glycol, ethyl cellulose,ethyl cellulose/ethanol mixture, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, glycerol monostearate, Eudragit®E. In addition,hydrogels from azo compounds are possible, for example N-substitutedmethacrylamide, N-tertbutylacrylamide, acrylic acid in the presence of4,4′-bis(methacryloylamino)azobenzenes, 4,4′-bis(Nmethacryloyl-6-aminohexanoylamino)azobenzene or 3,3′,5,5′-tetrabromo-4,4,4 ′4 ′-tetra(methacryloylamino)azobenzene. Examples ofother compounds are unbranched polymer precursors, for examplecontaining N,N-dimethylacrylamide, N-tertbutylacrylamide, acrylic acid,N-methacryloylglycylglycine p-nitrophenyl ester, cross-linked bysuitable crosslinkers, for exampleN,N′-(ω-aminocaproyl)-4,4′-diaminoazobenzene and polymers containing azocompounds, for example 2-hydroxyethyl methacrylate,4-(methacryloyloxy)azobenzene, N-(2-hydroxypropyl)methacrylamidecopolymers, copolymers containing styrene and 2-hydroxyethylmethacrylatecrosslinked by, for example, 4,4′-divinylazobenzene orN,N′-bis(β-sterylsulfonyl)-4,4′-diaminoazobenzene. Also,poly(ether-ester)azo polymers can also be used according to theinvention, for example copolymers containing4-[4-[(6-hydroxyhexyl)oxy]phenyl]azobenzoic acid and16-hydroxyhexadecanoic acid, copolymers containing4-[2-[2-(2-hyrdoxyethoxy)ethoxy]ethoxy]benzoic acid,4-[4-[2-[2-(2hydroxyethoxy)ethoxy]ethoxy]phenyl]azobenzoic acid and16-hydroxyhexadecanoic acid or 12-hydroxydodecanoic acid and segmentedpolyurethanes containing m-xylene diisocyanate,3,3′-dihydroxyazobenzene, polyethylene glycol or 1,2-propanediol. Inaddition, usable compounds are azo-compound-containing polyamides orcopolymers of 4-[4-(chlorocarbonyl)phenyl)]azobenzoyl chloride andα,(ω-bis(aminopropyl)poly(tetramethylene oxide) and copolymers of4-[4-chlorocarbonyl)phenyl]azobenzoyl chloride and Jeffamine ED-600.

In addition, pectins are used, which can be additionally coated orembedded in a matrix, for example, methoxy pectin, amidated pectin,calcium pectate, pectin in combination with ethyl cellulose (Aquacoat,Surelease), acrylic ester polymers (Eudragit RS30D, Eudragit NE30D). Inaddition, combinations of pectins with other dietary fibers are used.Examples of dietary fibers are (galactomannan) or chitosan, the dietaryfibers themselves in turn being able to be coated or a constituent of amatrix. In this case the following substances are used as film-formers:polymethacrylate solutions, copolymers containing polyurethane and di-,oligo- or polysaccharides (galactomannans) and ethylgalactomannans oracetylgalactomannans. In addition, cyanoacrylate, inulin, inulinsuspensions containing Eudragit-RS, methacrylated inulin, chondroitinsulfate, chondroitin polymers containing 1,12-diaminododecane anddicyclohexylcarbodiimide, amorphous amylose or amorphous amylosetogether with other film-forming polymers are used as film-former. Inaddition, dextrans can be used which can be crosslinked in various ways,for example with diisocyanates, fatty acid esters, for example lauricacid, glutaraldehyde. conjugates of biphenylacetic acid andβ-cyclodextrin, films of β-cyclodextrins with methacrylic acidcopolymers or acrylic acid polymers with disaccharide side groups arealso used according to the invention.

The choice of compounds and their many possible combinations maketargeted release of the sponge-like structure in the large intestinepossible.

The invention is described in more detail below with reference to thefollowing example:

Preparation of Alginate Sponges

Into each of the recesses of a microtiter plate (diameter 16 mm, height20 mm) are pipetted 0.5 ml of a 1% strength sodium alginate solution(w/v) and 0.5 ml of distilled water and, with intensive stirring, a 0.2%strength calcium gluconate solution (w/v) are added to each. Thehydrogels thus produced are frozen overnight at −20° C. and are thenfreeze-dried at 0.007 mm Hg (column mercury) and −60° C. Thefreeze-dried small sponges are removed from the microtiter plate andimmersed for 30 seconds in 0.1 molar hydrochloric acid. The hydrochloricacid is removed by rinsing with distilled water. The small sponges aredried in a drying cabinet at 30° C. and are then pressed.

What is claimed is:
 1. A composition for oral intake, the compositioncomprising: stably crosslinked uronic-acid-containing polysaccharideshaving a sponge structure; wherein the uronic-acid-containingpolysaccharides are only slightly soluble or of low absorbability inwater and/or gastrointestinal liquids; wherein theuronic-acid-containing polysaccharides are crosslinked to one another byionic bonds and by covalent bonds.
 2. The composition according to claim1, wherein the uronic-acid-containing polysaccharides are selected fromthe group consisting of alginic acids, pectins, xanthan, tragacanth, andchondroitin sulfate.
 3. The composition according to claim 1, whereinthe uronic-acid-containing polysaccharides are present in the form ofsalts.
 4. The composition according to claim 1, wherein the covalentbonds are ester bonds catalyzed by a mineral acid.
 5. The compositionaccording to claim 1, wherein active compounds are introducedinto/applied onto the sponge structure or encase the sponge structure.6. A process for preparing a composition according to claim 1, whereinpolyuronic-acid-containing polysaccharides a) are crosslinked via ionicbonds, b) are frozen, c) are freeze-dried, d) are stably crosslinked viacovalent bonds and e) are then dried and f) are, if appropriate,pressed.
 7. The process according to claim 6, wherein the unbranchedpolyuronic-acid-containing polysaccharides used are selected from thegroup consisting of alginic acids, pectins, xanthan, tragacanth, andchondroitin sulfate.
 8. The process according to claim 6, wherein theuronic-acid-containing polysaccharides are present in the form of salts.9. The process according to claim 7, wherein the alginic acids or saltsof the alginic acids are used in concentrations of 0.3 to 10% a byweight.
 10. The process according to claim 9, wherein the alginic acidsor salts of alginic acids are used in concentrations of 0.5 to 5% byweight.
 11. The process according to claim 10, wherein the alginic acidsor salts of alginic acids are used in concentrations of 1 to 3% byweight.
 12. The process according to claim 6, wherein the covalent bondsare ester bonds catalyzed by a mineral acid.
 13. The process accordingto claim 12, wherein the mineral acid is used in a concentration of 0.1mol/1.
 14. The process according to claim 6, wherein the mineral acid isa hydrochloric acid solution.